Preparation of pyrroles by cyclization of azines

ABSTRACT

ALKYL SUBSTITUTED PYRROLES AND PYRAZOLINES ARE PREPARED BY TREATING A KETAZINE OR ALDAZINE WITH A METAL HALIDE OF THE FORMULA MX2 WHERE M IS COBALT OR NICKEL AND X IS A HALOGEN A TEMPERATURE OF 10 TO 300*C.

3,772,328 PREPARATION OF PYRROLES BY CYCLIZATION F AZINES Christian H. Stapfer, Newtown, and Richard W. DAndrea, New Hope, Pa., assignors to Cincinnati Milacron Chemicals Inc., Reading, Ohio No Drawing. Original application Feb. 26, 1970, Ser. No. 14,628, now Patent No. 3,666,772. Divided and this application Dec. 3, 1971, Ser. No. 204,691

Int. Cl. (30711 27/20, 49/10 US. Cl. 260313.1 7 (Ilaims ABSTRACT OF THE DISCLOSURE Alkyl substituted pyrroles and pyrazolines are prepared by treating a ketazine or aldazine with a metal halide of the formula MX where M is cobalt or nickel and X is a halogen at a temperature of 10 to 300 C.

This is a division of application Ser. No. 14,628, filed Feb. 26, 1970, now Pat. 3,666,772.

The present invention relates to the preparation of alkyl substituted pyrroles and pyrazolines.

Numerous procedures have been proposed in the past for preparing alkyl pyrroles and alkyl pyrazolines. However, such procedures are expensive and the yields of the desired product are low.

It is an object of the present invention to develop an improved process for preparing alkyl pyrroles.

Another object is to develop an improved process for preparing alkyl pyrazolines.

Still further objects and the entire scope of applicability of the present invention will become apparent from the detailed description given hereinafter; it should be understood, however, that the detailed description and specific examples, while indicating preferred embodirnents of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

It has now been found that these objects can be attained by (1) treating an azine of the formula where R and R are hydrogen or lower alkyl, e.g., alkyl of 1 to 4 carbon with a catalytic amount of a metal halide of the formula MX where M is cobalt or nickel and X is a halogen to form a Z-pyrazoline of the formula where R and R are hydrogen or lower alkyl of 2 or more, e.g., 4 or 5 carbon atoms and R and R are lower alkyl, e.g., 1 to 4 carbon atoms or R together with R CH -form a ring with 6 methylene units and/or R United States Patent 6 together with R cH -forms a ring with 6-methylene units with a catalytic amount of a metal halide of the formula MX with elimination of one mole of ammonia to form a substituted pyrrole of the formula iir ri;

where R and R are lower alkyl, e.g., of 1 to 4 carbon atoms and R and R are hydrogen or lower alkyl of at least 2 carbon atoms, e.g., 2 or 4 carbon atoms or R together with R forms a ring with 6 methylene units and/or R together with R forms a ring with 6 methylene units.

Both reactions (1) and (2) can be carried out over a wide range of temperatures, e.g., 10 to 300 C., preferably 20 to 200 C.

As the catalyst MX these can be used: CoCl CoI CoF CoBr NiCl NiBr NiF or NiI As the starting azine, these can be used acetaldazine, propionaldazine, butyraldazine, isobutyraldazine, valeraldazine, acetone azine, methyl ethyl ketazine, diethyl ketazine (3-pentanone azine), methyl propyl ketazine, methyl butyl ketazine, dibutyl ketazine, dipropyl ketazine, ethyl butyl ketazine, ethyl propyl ketazine, propyl butyl ketazine, cyclohexanone azine.

The cobalt and nickel halide catalysts are generally used in an amount of 0.001 to 5 parts per parts by weight of azine. However, the proportion is not critical, e.g., the azine can be passed over the supported catalyst so that 10, 50 or more parts of catalyst are present per part of azine, although the use of such large amounts of catalyst is not the most economical method of operation.

Examples of compounds which can be prepared according to the present invention are 3,5,5-trimethyl-2-pyrazoline, S-methyl-Z-pyrazoline, 3,S-diethyl-S-methyl-Z-pyrazoline, 3,5-dibutyl-S-methyl-Z-pyrazoline, 3-butyI-S-methyl-pyrazoline, 3-butyl-5-propyl-S-methyl-Z-pyrazoline, 3-isopropyl-S-methyl-Z-pyrazoline, 3-ethyl-S-methyl-Z-pyrazoline, 3,S-dimethyl-Z-pyrazoline, 3,4-dimethyl pyrrole, 2,5-diethyl-3,4-dimethyl pyrrole, octahydrocarbazole, 2,3,4,5-tetraethyl pyrrole, 2,5-dibutyl-3,5-dimethyl pyrrole, 2-propyl-3,4-diethyl pyrrole, 3,4-di(isopropyl) pyrrole, 2,5-diethyl-3,4-dibutyl pyrrole.

In general, the yields of pyrazolines are higher than the yields of pyrrole. This is apparently due to the fact that in the reaction to form the pyrrole, the pyrrole ammonia is eliminated quantitatively and the hydrogen abstraction which takes place is accompanied by the formation of polymeric materials which reduces the yields.

It has further been observed that whenever both a methyl and a methylene group are concurrently adjacent to the nitrogen bonded carbon atoms, as in the case of methyl ethyl ketazine (2-butanone azine), the methyl group prevails and the intermediate transition metal complex formed favors the formation of a pyrazoline.

Unless otherwise indicated, all parts and percentages are by weight.

EXAMPLE 1 0.5 g. of anhydrous cobalt (II) chloride was added to 112 g. of acetone azine and the reaction mixture was kept at reflux for 24 hours. Upon fractional distillation 86 g. (77% yield) of pure 3,5,5-trimethyl-2-pyrazoline was isolated. This compound was characterized by its physical constants M.P.=8 C.; B.P. 160:156160 C.

Calculated for C H N (percent): C, 64.28; H, 10.80; N, 25.00. Found (percent): C, 64.32; H, 10.75; N, 24.95.

EXAMPLE 2 84 g. of acetaldazine was refluxed for 12 hours in presence of 0.01 g. of nickel (II) chloride and after fractional distillation, 42 g. (50% yield) of -methyl-2-pyrazoline, B.P. 55=73 C. The picrate of the pyrazoline had a M.P. of 127 C.

The pyrazoline compound was identical to a sample of 5-methyl-2-pyrazoline prepared by other known synthetic routes.

EXAMPLE 3 A mixture of 140 g. of methylethyl ketazine and 1 g. of cobalt (II) bromide was refluxed for 24 hours according to the general procedure of the proceding examples. After the usual distillation under vacuum, 88.6 g. (63% yield) of pure 3,5-diethyl-5-methyl-2-pyrazoline boiling at 195-200 C./760 mm. Hg was obtained.

Calculated for C H N (percent): C=68.6; H=11.4; N=20.0. Found (percent): 0:690; H=11.4; N=19.7.

EXAMPLE 4 The general procedure of Example 4 was adopted for the preparation of 49 g. (36% yield) of 3,4-dirnethyl pyrrole from 112 g. of propional azine and 1.0 g. of methyl-2,5 diethyl pyrrole, B.P. =155 C., was isolated. nickel (II) bromide. B.P. =192 C.

EXAMPLE 6 A mixture of 192 g. of cyclohexanone azine and 1.0 g. of anhydrous nickel (II) chloride was maintained under agitation at 200 C. for 24 hours. Upon cooling the reaction mixture crystallized and upon recrystallization from petroleum ether 145 g. (83% yield) of pure octahydrocarbazole was isolated. M.P. =-1 C.; picrate M.P.= 1345 C.

Calculated for C H N (percent): 0:82.24; H=9.76; N=7.99. Found (percent): 0:81.88; H=9.69; N=7.99.

What is claimed is:

1. A process for the cyclization of an aldazine or ketazine to form a pyrrole which comprises treating (1) an azine of the formula where R and R are hydrogen or lower alkyl of at least 2 carbon atoms, R; and R are lower alkyl or at least one of R together with R CH or R together with R CH forms a ring with 6 methylene units with (2) a metal halide of the formula MeX where Me is cobalt or nickel and X is a halogen and wherein MeX is used in an amount of from 0.001 part per 100 parts of azine up to 50 parts per part of azine and the reaction is carried out at a temperature of 10 to 300 C.

2. A process according to claim 1 wherein X is chlorine, bromine or iodine.

3. A process according to claim 1 wherein the azine is cyclohexanone azine and the product is octahydrocarbazole.

4. A process according to claim 1 wherein the azine has the formula where R and R are hydrogen or lower alkyl of at least 2 carbon atoms and R and R are lower alkyl and the product is an alkyl pyrrole of the formula are hydrogen and R and R are ethyl and the product is 3,4-dimethyl pyrrole.

References Cited Hollins, The Synthesis of Nitrogen Ring Compounds (1924 p. 80.

JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R. 

